Summary of Work: A series of projects are ongoing with the cyclooxygenase (COX) knock-out mice. 1) Tumorigenesis in the COX-1 and COX-2 null strains has been studied using the DMBA/TPA two stage skin model and the Apc (min) mutant intestinal polyposis model. Skin papilloma formation was reduced by 70% in both of the knockout strains compared to the control. This appears to be due to alterations in several homeostatic factors, including rates of epidermal replication and apoptosis. COX-1 and COX-2 mice have been bred to APC (min) mice which are susceptible to spontaneous adenopolyposis of the colon. The deficiency of either COX isoform reduces colon carcinogenesis by about 80% in this background. 2) Using the air pouch model for inflammation, differences in the responses of the COX-1 and -2 mice to inflammatory chemical agents have been observed in production of PGE2, and in the number and type of cells recruited. 3) Mice deficient in both COX-1 and COX-2 have been produced. These mice, and mice carrying only a single copy of one of the COX genes, are being used to determine the physiological roles of the individual COX isoforms.